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. 2000 Mar;105(5):615-23.
doi: 10.1172/JCI8437.

Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism

S Yu  1 , O Gavrilova, H Chen, R Lee, J Liu, K Pacak, A F Parlow, M J Quon, M L Reitman, L S Weinstein
Affiliations

Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism

S Yu et al. J Clin Invest. 2000 Mar.

Abstract

Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.

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Figures

Figure 1
Figure 1
Weight curves of m–/+ and +/p– mice. To control for genetic background variability, the weight of each mutant mouse is expressed as a percent of the weight of wild-type littermates of the same age and sex. The data (male m–/+, filled square; female m–/+, open square; male +/p–, filled triangle; female +/p–, open triangle; n = 10–39 per group) were binned using 1-week intervals and expressed as mean ± SEM. Because mutant mice are short, a normal BMI corresponds to a weight of approximately 80% of wild-type littermates (see the text and Table 3). By 60 days, all m–/+ mice weighed greater than 80% of wild-type, whereas all +/p– mice weighed less than 80% of wild-type.
Figure 2
Figure 2
Fat accumulation and UCP expression in adipose tissue. (a) Histological sections of interscapular BAT and subcutaneous WAT after hematoxylin and eosin staining from 2-day-old mice. In m–/+ mice (right), there is markedly increased lipid accumulation in both BAT and WAT when compared with wild-type mice (center, +/+). In contrast, there is markedly reduced lipid accumulation in both BAT and WAT in +/p– mice (left). Original magnification, ×100. (b) UCP1 (left) and UCP3 (right) mRNA levels in BAT from +/p– (filled bar) and m–/+ (open bar) expressed as percent of wild-type littermates (UCP1, n = 5 pairs of mice in each group, m–/+ versus wild type, P = 0.056; UCP3, n = 4 pairs for +/p– and 3 pairs for m–/+).
Figure 3
Figure 3
Correlation between leptin and BMI in m–/+, +/p–, and wild-type mice. Serum leptin levels of individual adult wild-type (filled circles, open circles), +/p– (filled triangles, open triangles), and m–/+ (filled squares, open squares) mice are plotted as a function of their BMI. Male (filled circle, filled triangle, filled square) and female (open circle, open triangle, open square) mice followed similar curves.
Figure 4
Figure 4
Food intake and metabolic studies in m–/+ and +/p– mice. (a) Food intake in 6- to 8-week-old male mice over a 7-day period normalized to (body weight)0.75 (–62). Data for mutant mice are shown as open bars, and data for wild-type mice are shown as filled bars (n = 6–8 mice per group). (b) Resting oxygen consumption at 21° C in 7-month-old female mice measured over a 24-hour period (n = 5 pairs of mice in each group). (c) Total and ambulating activity measured over 24 hours in mice studied in b. (d) Resting oxygen consumption at 30° C of 6- to 8-week-old female mice before (filled bars) and after (open bars) administration of a maximal dose of CL316243 (1,000 μg/kg intraperitoneally; n = 5 mice per group). For each group, the metabolic rate in the absence of agonist expressed as a percent of maximal metabolic rate is shown above. (e) Resting oxygen consumption in 6- to 8-week-old female m–/+ (open bars) and wild-type littermates (filled bars; n = 5 pairs) at 21° C is shown at the left. To the right is resting oxygen consumption in similar mice at 30° C treated with the indicated intraperitoneal doses of CL316243 (n = 4–10 pairs of mice at each dose). (f) Serum FFAs (left panel) and glycerol (right panel) in 6-hour fasted 13-week-old male m–/+ mice (open bars) and wild-type littermates (filled bars) before and 15 minutes after administration of a maximal dose of CL316243 (1,000 μg/kg intraperitoneally; n = 5 mice per group). In all panels, data are expressed as the mean ± SEM, and an asterisk indicates P < 0.05 versus wild-type littermates by t test.
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